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Safety and cognitive pharmacodynamics following dose escalations with 3-methylmethcathinone (3-MMC):a first in human, designer drug study
No full text3-Methylmethcathinone (3-MMC) is a designer drug that belongs to the group of synthetic cathinones. The compound has been scheduled in many jurisdictions because of public health concerns associated with excessive use. To date, there are no clinical studies that have evaluated the risk profile of 3-MMC in the recreational range of low to moderate doses. The current, first-in-human study (N = 14) assessed the impact of three escalating doses of 3-MMC (25, 50 and 100 mg) on vital signs, neurocognitive function, state of consciousness, appetite and drug desire, in a cross-over, placebo-controlled trial. A battery of neurocognitive tests and questionnaires as well as measures of vital signs were repeatedly administered up to 5 h after dosing. Overall, 3-MMC caused dose-dependent increases in heart rate and blood pressure, though not of clinical significance, and feelings of subjective high. Additionally, 3-MMC induced dose-related enhancement of task performance across several neurocognitive domains, including processing speed, cognitive flexibility, psychomotor function, attention and memory. Impulse control was not affected by 3-MMC. Participants also reported mild increases in dissociative and psychedelic effects, decreased appetite, and gave greater ratings of liking and wanting for 3-MMC that were transient over time. Overall, the cardiovascular, psychostimulant and psychotomimetic profile of 3-MMC appears consistent with that of compounds structurally related to amphetamine. It is concluded that low to moderate doses of 3-MMC were well tolerated and safe and that potential health risks might only occur at high or excessive doses of 3-MMC
Child Work in Developing Countries:Revisiting the Differences and Similarities Between Income-Generating and Care and Domestic Work
No full textChild work is still widely prevalent in many countries: it refers to both income-generating activities and unpaid care and domestic activities. However, the existing literature and international statistical standards either aggregate these two forms of work or focus exclusively on income-generating work. In this paper, we show the differences and similarities in the prevalence and determinants of paid and unpaid child work using data from nationally representative household surveys for 34 developing countries, representing over 900 million people. We find that across countries, care and domestic work is more prevalent among children and adolescents aged five to 17 years, but less intensive than income-generating work. The age and sex of the child matters. Gender is diametrically associated to the two forms of work, while the likelihood of both increases with age. We observe variation in the sign and magnitude of caregiver and household-level coefficients between countries, however in most countries household composition factors proxying care supply have opposite effects on the two forms of child work, while household infrastructure affects both forms of work in the same direction. The findings call for distinctly measuring the two forms of child work and addressing their respective determinants through context-specific interventions
Reproduction of (Un)-modernity at the site of the everyday:Knowledge production practices on 'migrant families' in the Netherlands
No full textThis paper examines how the everyday doing of 'migrant families' is described, problematized, and disciplined within knowledge production practices. Through a critical discourse analysis of research reports originating in the Netherlands and focused on migrant families, the paper explores the discursive constructions of 'modern' and 'unmodern' families, depicted in their doing of 'modern' and 'unmodern values', while highlighting the fluid and contested construction of modernity itself. By merging theoretical perspectives from critical migration studies, sociology of the everyday, and occupational science, the paper argues that the study and description of the everyday is yet another site where cultural assumptions and modernity logics are (re)produced and disseminated into practice in ways in which the everyday becomes the site of intensive harm. In turn, the implications of such discursive harm in the lives of those deemed 'unmodern' warrants further study
Aldolase B Deficient Mice Are Characterized by Hepatic Nucleotide Sugar Abnormalities
No full textHereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (Aldob-/-) were treated for four weeks with 5% mannose via the drinking water and compared to Aldob-/- mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated Aldob-/- mice when compared to water-treated wildtype mice (p = 0.002 and p = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-N-acetyl-beta-neuraminic acid, and CDP-ribitol (p = 0.002, p = 0.003, p = 0.002, p = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. Aldob-/- mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI.Trial Registration: PCT ID: PCTE0000340, this animal experiment is registered at ()
Body Composition in Cholangiocarcinoma Affects Immune Cell Populations in the Tumor and Normal Liver Parenchyma
No full textBackground: Due to malnutrition and tumor cachexia, body composition (BC) is frequently altered and known to adversely affect short- and long-term results in patients with cholangiocarcinoma (CCA). Here, we explored immune cell populations in the tumor and liver of CCA patients with respect to BC. Methods: A cohort of 96 patients who underwent surgery for CCA was investigated by multiplexed immunofluorescence (MIF) techniques with computer-based analysis on whole-tissue slide scans to quantify and characterize immune cells in normal liver and tumor regions. BC was characterized by obesity, sarcopenia, myosteatosis, visceral obesity and sarcopenic obesity. Associations between BC and immune cell populations were determined by univariate and multivariable binary logistic regressions. Results: BC was frequently altered in intrahepatic CCA (iCCA, n = 48), with 47.9% of the patients showing obesity, 70.8% sarcopenia, 18.8% sarcopenic obesity, 58.3% myosteatosis and 54.2% visceral obesity as well as in perihilar CCA (pCCA, n = 48) with 45.8% of the patients showing obesity, 54.0 sarcopenia, 14.6% sarcopenic obesity, 47.9% myosteatosis and 56.3% visceral obesity. From an immune cell perspective, independent associations within the tumor compartment were observed for iCCA (myosteatosis: TIM-3+CD8+cells; obesity: PD-1+TIM-3+CD4+cells) and for pCCA (myosteatosis: PD-L2+CD68-cells and CD4+cells). Further, independent associations were observed within the normal liver parenchyma for iCCA (visceral obesity: PD-1+PD-L1+PDL2+CD68+cells) and for pCCA (sarcopenia: CD68+cells and TIM-3+CD8+cells; visceral obesity: ICOS+TIGIT+CD8+cells and sarcopenic obesity: PD-1+PD-L1+PD-L2+CD8+cells). Conclusion: This is the fi rst systematic analysis of the association of BC and immune cells in cholangiocarcinoma showing a strong association between BC and distinct immune cell populations within the tumor itself as well as within the normal parenchyma
Facilitators and barriers affecting the implementation of e-health for chronic respiratory diseases in remote settings:a qualitative evidence synthesis
No full textBackgroundChronic respiratory diseases are important causes of disability and mortality globally. Their incidence may be higher in remote locations where healthcare is limited and risk factors, such as smoking and indoor air pollution, are more prevalent. E-health could overcome some healthcare access obstacles in remote locations, but its utilisation has been limited. An improved understanding of barriers and facilitators to the implementation of e-health in remote locations could aid enhanced application of these approaches.MethodsWe performed a qualitative evidence synthesis to explore factors affecting the successful implementation of e-health interventions in remote locations for patients with chronic respiratory diseases. We searched PubMed, CINAHL, Embase, Web of Science and PsycINFO databases for qualitative and mixed-methods studies. Studies were assessed by two researchers, and 41 studies were included in the synthesis. Quality was assessed via the CASP-tool. Findings were coded with Atlas.ti software and categorised based on an adapted Digital Health Equity Framework.ResultsNineteen themes were identified across five levels (individual, interpersonal, community, society and technology), with associated facilitators and barriers for implementation. An important facilitator of e-health was its role as a tool to overcome obstacles of distance and to increase access to care and patients' self-efficacy. Potential barriers included the reduction of in-person interactions and an increased burden of work for healthcare providers. Good quality, usability, adaptability and efficacy of e-health interventions were important for implementation to be successful, as were adaptation to the local setting - including culture and language -and involvement of relevant stakeholders throughout the process.ConclusionsSeveral factors affecting the implementation of e-health in remote and rural locations for patients with chronic respiratory disease were identified. Intervention objectives, target population, geographical location, local culture, and available resources should be carefully considered when designing an e-health intervention. These findings can be used to inform the successful design and implementation of future e-health interventions
Unravelling Education Needs for Clinical Practice Guideline Development:A Survey Performed in the Netherlands
No full textObjectiveThe development of clinical practice guidelines (CPG) has evolved into a rigorous and complex process. There is a need for training of CPG developers including methodologists, panel members and patient representatives. This study explored the educational needs and experiences of CPG developers, with specific attention to the patient perspective and economic considerations.Study Design and SettingAn anonymised mixed-method survey was distributed among CPG developers and panel members in the Netherlands. The survey, developed in collaboration with Dutch CPG development organisations and patient organisations, aimed to capture insights into the developers' roles, training needs, and the incorporation of economic considerations and patient perspectives in CPG development. Data analysis involved qualitative content analysis and descriptive quantitative analysis.ResultsA total of 271 responses were analysed. Respondents described role-specific tasks and tasks overlapping between roles. Experience, guidance, and training influenced the respondents' feeling of preparedness for their tasks. Respondents expressed the need for content-related training, including CPG development methodology. They also raised the importance of process-related topics in training, such as the inclusion of different perspectives and responsibilities during CPG development. About half of the respondents (46%) indicated that economic considerations were included in their CPGs, however, there was no uniformity in approach. The patient perspective was included by 89% of the respondents, also in varying manners. Overall, respondents underscored the importance of both topics in CPG development (training) to ensure a future-proof healthcare system.ConclusionThis study underscores the importance of tailored CPG development training programmes addressing the specific competencies required for the different roles in CPG development. Thereby, recognising a holistic approach encompassing both content- and process-related aspects. Addressing economic considerations and the patient perspective in training will contribute to CPGs that support a patient-centred and sustainable healthcare system
Patients perspectives on integrating eHealth in regular care pathways for atrial fibrillation:evaluating photoplethysmography for remote self-assessment
No full textAIMS: Smartphone applications for heart rate and rhythm assessment are increasingly used for the management of atrial fibrillation (AF). Although the use of a photoplethysmography (PPG)-based smartphone application with subsequent (tele)consultations for AF management has been proven feasible in the TeleCheck-AF project, specific needs, and expectations of patients with AF are unclear. The aim of this study is to evaluate patients' perspectives on the use of remote PPG-based electronical health (eHealth) integrated in regular care pathways for AF. METHODS AND RESULTS: A qualitative study was conducted among patients with known AF, who have used a PPG-based smartphone application around scheduled (tele)consultations. Semi-structured interviews were audio-recorded and transcribed verbatim. Data were analysed according to conventional content analysis.In total, 14 patients were interviewed. Five main themes were defined after analysis, i.e. smartphone application usability, requirements for eHealth implementation, remote self-assessment, patient engagement, and blended care (i.e. combining digital and face-to-face care). Overall, the participants were positive about the use of the PPG-based smartphone application and subsequent (tele)consultation. Using this application made the participants feel involved and led to active participation. In addition, the healthcare provider-patient relationship appeared an important aspect for adequate implementation. Particularly, timely consultation was found important, to discuss the results with their healthcare provider. CONCLUSION: The results of this study emphasize the importance of blended care for the implementation of remote PPG-based eHealth in AF management. The use of a PPG-based smartphone application in regular care can support patient engagement and subsequently the process of shared decision making.</p
European Guideline on Chronic Nausea and Vomiting-A UEG and ESNM Consensus for Clinical Management
No full textIntroductionChronic nausea and vomiting are symptoms of a wide range of gastrointestinal and non-gastrointestinal conditions. Diagnosis can be challenging and requires a systematic and well-structured approach. If the initial investigation for structural, toxic and metabolic disorders is negative, digestive motility and gut-brain interaction disorders should be assessed. United European Gastroenterology (UEG) and the European Society for Neurogastroenterology and Motility (ESNM) identified the need for an updated, evidence-based clinical guideline for the management of chronic nausea and vomiting.MethodsA multidisciplinary team of experts in the field, including European specialists and national societies, participated in the development of the guideline. Relevant questions were addressed through a literature review and statements were developed and voted on according to a Delphi process.ResultsNinety-eight statements were identified and voted following the Delphi process. Overall agreement was high, although the grade of scientific evidence was low in many areas. Disagreement was more evident for some pharmacological treatment options. A diagnostic algorithm was developed, focussing on the differentiating features between gastrointestinal motility and gut-brain interaction disorders with predominant nausea and vomiting.ConclusionThese guidelines provide an evidence-based framework for the evaluation and treatment of patients with chronic nausea and vomiting
Optimal designs for mixture choice experiments by simulated annealing
No full textMixture choice experiments investigate people's preferences for products composed of different ingredients. To ensure the quality of the experimental design, many researchers use Bayesian optimal design methods. Efficient search algorithms are essential for obtaining such designs. Yet, research in the field of mixture choice experiments is not extensive. Our paper pioneers the use of a simulated annealing (SA) algorithm to construct Bayesian optimal designs for mixture choice experiments. Our SA algorithm not only accepts better solutions, but also has a certain probability of accepting inferior solutions. This approach effectively prevents rapid convergence, enabling broader exploration of the solution space. Although our SA algorithm may start more slowly than the widely used mixture coordinate-exchange method, it generally produces higher-quality mixture choice designs after a reasonable runtime. We demonstrate the superior performance of our SA algorithm through extensive computational experiments and a real-life example